We recently completed a study showing that three distinct HLA alleles (B*27, B*57 and B*35Px) known to alter the overall rate of AIDS progression act during distinct intervals following HIV-1 infection. The discrete timing of HLA allele influence suggests alternative functional mechanisms in immune defense against this dynamic and chronic immunosuppressive disease. Thus far, HLA class I and class II genotyping have been completed on 1200 samples from the WIHS cohort and preliminary analysis of the data suggests there are a number of significant associations between particular HLA alleles and prevalent HPV infection as well as squamous intraepithelial lesions. We have just begun genotyping of the Guanacaste HPV cohort. With regards to allelic analysis of KIR genes, we have completed KIR3DL1 subtyping in our AIDS cohort (see "KIR gene polymorphism and its role in HIV-1 pathogenesis") and more recently, in our HCV cohort. Using normal blood donors that were typed in our laboratory, our collaborators at the NIDDK have found that NK cells from subjects with the KIR2DL3/HLA-C group 1 genotype exert stronger cytotoxicity, and stronger and more rapid cytokine production in response to influenza A virus infection than NK cells from KIR2DL1/HLA-C group 2 subjects. These functional differences likely explain the protective genetic effect of KIR2DL3/HLA-C group 1 against HCV that we previously reported. Our studies on TSG101, which are now complete, show that two non-coding single nucleotide polymorphism (SNP) variants associate with differences in HIV viral load dynamics, in CD4 T cell decline, and, correspondingly, with rate of AIDS progression after infection. We identified two polymorphic sites in the 5' area located at positions -183 and +181 relative to the translation start, that specify three haplotypes termed A, B, and C. Haplotype C was associated with relatively rapid AIDS progression while haplotype B was associated with slower disease progression. Both effects were dominant over the intermediate haplotype A. The data raise the hypothesis that noncoding variation in TSG101 affects the efficiency of TSG101-mediated release of viral particles from infected cells, thereby altering levels of plasma viral load and subsequent disease progression.